SQ3370

P1/2, N=53, Terminated, Shasqi, Inc. | N=145 --> 53 | Recruiting --> Terminated; Sponsor's decision

The first-in-class Click Activated Protodrugs Against Cancer-based cancer therapeutic SQ3370 uses a clickable pretargeting agent that reacts with a chemically attenuated clickable payload of doxorubicin (Dox) and releases the active cytotoxic drug in situ. SQ3370, the first demonstration of click chemistry within the human body in a clinical setting, facilitated the delivery of chemotherapy to tumors and unlocked additional biological effects such as favorable immune responses that may benefit patients with metastasis. Consistent safety, toxicology, pharmacokinetic, and immune activation results observed across species highlight the translatability of the technology and position click chemistry as a powerful new modality for the development of targeted cancer therapeutics.

Objective clinical activity was observed, but ORR was comparable to standard Dox. ▪ SQ3370 is a click chemistry-enabled, pre-targeting therapeutic and the first use of in vivo click chemistry in humans ▪ SQ3370 up to15x standard doxorubicin dose in patients with solid tumors was safe with no DLTs reported▪ In Phase 2a, SQ3370 provided an unconfirmed objective response rate of 14.3% and disease control rate of 71.4% in patients with advanced sarcomas▪ Tumor size reductions seen in both injected and non-injected lesions, potentially due to systemic anti-tumor responses.

Our assessment of immune changes after SQ3370 treatment confirms that observations in preclinical models are translatable to humans, as similar T-cell supportive immune changes were observed in syngeneic tumor models with SQ3370. Consistency between immune responses in clinical and preclinical samples underlines the translatability of the click chemistry-based drug and suggests that its broad therapeutic potential may be further enhanced with combined immunotherapies.

The lead candidate SQ3370 consists of an intratumorally (IT) injected tetrazine (Tz)-modified biopolymer and an intravenously (IV) administered trans-cyclooctene (TCO)-modified doxorubicin (Dox) protodrug. Anti-tumor activity was observed in multiple preclinical models for the TCO-MMAE protodrug in combination with both biopolymer and Fab targeting agents. These results highlight the power of click chemistry to activate a protodrug at the tumor site, independent of tumor biology, the molecular format or delivery method of the targeting agent.